Intermediates useful in the synthesis of vitamin a

ABSTRACT

SULPHONES OF THE FORMULA:   1,3,3-TRI(ME-),2-(Q-OOC-CH=C(-ME)-CH(-SO2-R)-CH2-CH=   C(-ME)-CH=CH-)CYCLOHEXENE   IN WHICH R IS ARYL AND Q IS HYDROGLEN OR HYDROCARBON RADICAL, WHICH ARE MADE BY REACTING, PREFERABLY AT LOW TEMPERATURE. A HALIDE OF THE FORMULA:   1,3,3-TRI(ME-),2-(X-CH2-CH=C(-ME)-CH=CH-)CYCLOHEXENE   AND A SULPHONE OF THE FPRMULA:   R-SO2-CH2-C(-ME)=CH-COO-Q   ARE USE FUL INTERMEDIATES FOR PRODUCING VITAMIN A INTO WHICH THEY MAY BE CONVERTED BY SAPONIFICATION, DESUPHONATION, AND REDUCTION.

States Patent INTERMEDIATES USEFUL IN THE SYNTHESIS OF VITAMIN A MarcJulia, Paris, France, assignor to Rhone-Poulenc S.A., Paris, France NoDrawing. Original application Aug. 4, 1971, Ser. No. 169,114, now PatentNo. 3,748,347, dated July 24, 1973, Divided and this application Dec.29, 1972, Ser.

priority, applica$19i:)6France, Aug. 5, 1970, 3 Int. Cl- C07c149/40 U.S.Cl. 260-470 V ZClaims ABSTRACT OF THEDISCLOSURE i Sulphones of theformula:

Me V

in which R is aryl and Q is hydrogen or a hydrocarbon radical, which aremade by reacting, preferably at low temperature, a halide of theformula:

are useful intermediates for producing vitamin A into which they may beconverted by saponification, desulphonatiomand reduction. 1

"This is a division of application Ser. No. 169,114, filed Aug. 4, 1971,now U.S.Pat. 3,748,347. V

The present invention relates to intermediates useful in the synthesisof 'vitamin A.

The presentinvention provides, as new compounds useful as intermediatesin the synthesis of vitamin A, the sulphones of the formula: w

in whch X represents a chlorine, bromine or iodine atom, hydrogen atomor a monovalent hydrocarbon radical. R can in particular representnaphthyl, phenyl or alkylphenyl, in which the alkyl is preferably of 1to 4 carbon atoms, such as p-toluyl. Q can be, for example, an alkyl,cycloalkyl, aryl or aralkyl radical, but is preferably an alkyl radicalof 1 to 4 carbon atoms, such as methyl or ethyl.

The sulphones of Formula I are obtained in accordance with a feature ofthe invention by reaction of a halide of the formula:

Me Me Me in which X represents a chlorine, bromine with a sulphone ofthe formula:

Me (III) in which R and Q have the meanings given above. It is to beunderstood that the Formulae I and II do not necessarily representsterically pure products, but can represent mixtures of cis and transisomers.

The reaction of the halide of Formula II with the sulphone of Formula HIis preferably carried out at between -40 and 0 C., and usually atbetween 35 and 25 C. It is advantageous to carry out the reaction in thepresence of a solvent, especially an ether, such as tetrahydrofuran ordioxane, or another 'aprotic polar solvent, such as dimethylformamide,dimethylsulphoxide, hexamethylphosphorylamide or N-methylpyrrolidone.Generally, the process is carried out in the presence of an acceptor,e.g. an alkali metal butylate, for the hydrogen halide liberated.Usually, a solution of the halide of Formula II is slowly added to themixture of the other constituents of the reaction mixture. After thereaction and after the usual preliminary purification treatments, thesulphone of Formula I may be isolated in the pure state, for example bychromatography.

The halide of Formula II may be obtained by halogenation ofvinyl-B-ionol with a phosphorus trihalide.

The sulphones of Formula III which are new compounds, may be obtained byreaction of an alkali metal sulphinate of Formula RSO M, in which Mrepresents an alkali metal, with a 'y-halogenosenecioate of a nonvalenthydrocarbon radical, which is in turn obtainable by halogenation of thecorresponding senecioate with an N-halo genosu'ccinimide, for example bybromination with N- bromosuccinimide.

Desulphonation of the sulphones of Formula I in which Q representshydrogen, yields the acid of formula As is already known, reduction ofthe terminal carboxyl radical of this acid to give a hydroxymethylradical .CH OH yields vatmin A. When Q is in the sulphone of Formula Iis initially a hydrocarbon radical, the latter is first replaced byhydrogen by saponification.

.The example which follows illustrates the invention.

EXAMPLE The whole is cooled to 30 C. and a solution of 21.7 g. of aproduct containing 80% of the bromide of formula:

This sulphone-ester (13.6 g.) is isolated by chromatography on a silicacolumn.

The initial starting materials were synthesized as follows:

(a) The 80% pure bromide of Formula IV was obtained by bromination ofvinyl-fl-ionol with phosphorus tribromide.

Anhydrous diethyl ether (2.5 cc.), pyridine (0.05 cc.) and vinyl-p-ionol(2.2 g.0.0l mol) of the formula:

are introduced into a flask equipped with a stirrer. The whole is cooledto 35 C. with stirring and a mixture of anhydrous diethyl ether (1 cc.)and phosphorus tribromide (0.9 g.) is added dropwise with stirring. Whenthe addition is complete, stirring is continued for a further 30 minutesat -35 C., and the temperature is .then allowed to rise to C., again andis kept at 0 (2., for one hour, with continued stirring.

The ether phase is decanted, the residue is washed with diethyl ether,and the ether layers are combined and washed with an ice-cold solutionof sodium bicarbonate. The aqueous layer is extracted with diethyl etherand the ether layer is rapidly washed with ice-cold water; the combinedether layers are dried over magnesium sulphate. After evaporation of theether at 0 C., a crude bromide (2.17 'g.), containing 80% of the bromideof Formula IV, is obtained. The yield of the bromide of Formula IV isthus 60% based on the vinyl-p-ionol introduced. This bromide is notstable in the pure state and at ambient temperature. It is desirabletherefore to store it in solution in diethyl ether under nitrogen at atemperature below 0 C. I

(b) Ethyl 'y-(phenylsulphonyl)senecioate was prepared by reaction ofsodium phcnylsulphinate, PhSQ Na, with ethyl 'y-bromosenecioate.

Sodium phcnylsulphinate (16.4 g., 0.1 mol) is dissolved in anhydrousmethanol (35 cc.) in a three-neck flask equipped with a mechanicalstirrer. Ethyl 'y-bromosenecioate (20.7 g., 0.1 mol) is added dropwiseat-20"-C. A yellow precipitate appears. After completion of theaddition, the mixture is stirred for a further 10 minutes. The methanolis distilled off and progressively replaced by an equal volume of Water.After cooling, the aque+ one phase is extracted with diethyl ether andthe organic layers are combined. The whole is washed with 'water andthen dried over magnesium sulphate. A fter evaporation of the solvent,ethyl ry-(phenylsulphmiyl)senecioate (24.75 g.) (92% yield) is obtainedas a practically colorless liquid. w 2

Ethyl 'y-bromosenecioate (mixture of cis and trans isomers) was preparedby bromination of ethyl senecioate with N-bromosuccinimide, in a yieldof 67% based on the N-brornosuccinimide, by the method described by I.Ahmad et al. J. Chem. Soc. 1958 C to 187.

The final sulphone-ester of Formula I, in'which R represents a phcnylradical and Q represents an ethyl radical, can be used as follows:

10 g. of this sulphone-ester (0.021 mole) 20 cc. of 96% ethanol and 3.5g. of potassium hydroxide (0.064 mole) are kept at boiling temperatureunder reflux for two hours. After cooling the acid fraction (6.4 g.) isseparated in the usual manner. By recrystallization of'this acidfraction in petrol ether, 73 mg. of vitamine A acid of formula Me Me MeMe 0 Hd! one represents phenyl and Q represents ethyl.

References Cited I v UNITED STATES PATENTS I 3,437,685 4/1969 Brus't 2260 481 3,655,772 4/1972 Chang, et al. 260-607 A 3,726,884 4/ 1973Aichenegg, et al. 260-481 R LORRAINE A. WEINBERGER, Primary :Examiner P.J. KILLOS, Assistant Examiner us. 01. X.R. 260-515 M.

UNITED STATES PATENT OFFICE CERTIFICATE OF -CORRECTION Pavrmmo.3,804,882 Dated April 16, 1974 Inventor( a 'Marc JULIA It is certifiedthat error appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

In the Claim for Convention Prihrity appearing in the heading of thepatent, for "18906" as the French application number, read 28906 Signedand sealed this 19th day of November 1974.

(SEAL) Attest:

C. MARSHALL DANN soN JR." MCCOY M GIB c i signer of Patents AttestingOfficer RM P0-1050 0- 9) uscoMM-oc 60376-P69 I U.S. GOVERNMENT PRINTINGOFFICE I969 0-356-334,

